Role of amniotic fluid homocysteine level and of fetal 5, 10-methylenetetrahydrafolate reductase genotype in the etiology of neural tube defects

Am J Med Genet. 2000 Jan 3;90(1):12-6. doi: 10.1002/(sici)1096-8628(20000103)90:1<12::aid-ajmg3>;2-h.


A mutation in the gene 5,10-methylenetetrahydrofolate reductase (MTHFR), leading to altered homocysteine metabolism, has been identified in parents and fetuses with fetal neural tube defects. We sought to determine which is of greater importance in fetal neural tube defect formation: the fetal MTHFR mutation or elevated amniotic fluid homocysteine level. We retrieved stored amniotic fluid from cases of isolated fetal neural tube defect diagnosed from 1988 to 1998 (n = 80), and from normal controls matched for race, month and year of amniocentesis, and maternal age. The presence or absence of the 677C-->T mutation of MTHFR was determined and homocysteine levels were measured; cases and controls were compared. Significantly more cases than controls were heterozygous or homozygous for the 677C-->T MTHFR mutation (44% vs 17%, P < or = 0.001). Cases were also significantly more likely than controls to have an amniotic fluid homocysteine level above the 90th centile (>1.85 micromol per liter); 27% vs 10%, P = 0.02. Thirty one cases and 12 controls had an abnormal genotype; however, amniotic fluid homocysteine levels were not significantly different between these two groups (6/31, or 19% of cases had an elevated homocysteine compared to 1/12, or 8% of controls; P = 0.65). In contrast, 40 cases and 60 controls had a normal genotype; the neural tube defect cases had significantly higher homocysteine levels (13/40, or 32% of cases had an elevated homocysteine level compared to only 6/60, or 10% of controls; P = 0.008). Although both abnormal fetal MTHFR genotype and abnormal amniotic fluid homocysteine concentration are significantly associated with neural tube defects, the association with amniotic fluid homocysteine concentration is significant regardless of the fetal MTHFR genotype. The relationship between maternal and fetal homocysteine metabolism is complex.

MeSH terms

  • 5,10-Methylenetetrahydrofolate Reductase (FADH2)
  • Alanine / genetics
  • Amino Acid Substitution
  • Amniotic Fluid / metabolism*
  • Female
  • Homocysteine / metabolism*
  • Humans
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Neural Tube Defects / diagnosis
  • Neural Tube Defects / enzymology
  • Neural Tube Defects / etiology*
  • Neural Tube Defects / genetics
  • Oxidoreductases / genetics*
  • Point Mutation
  • Pregnancy
  • Valine / genetics


  • Homocysteine
  • Oxidoreductases
  • 5,10-Methylenetetrahydrofolate Reductase (FADH2)
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Valine
  • Alanine